Amrubicin ((+)-(7S,9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione) that is an anthracycline compound is known as an anti-cancer agent exhibiting less side effects in comparison with known anthracycline compounds such as doxorubicin and daunorubicin (Japanese Examined Patent Publication JP-B 3-5397).
Amrubicin is characterized by a stronger anti-cancer activity of its metabolite (amrubicinol: hydroxylated product at 13-position of the anthracycline skeleton) obtained by being readily reduced in vivo, than that of amrubicin itself. To the contrary, doxorubicin and daunorubicin do not have such characteristics (Cancer Chemother. Pharmacol., 30, 51–57 (1992)). In addition, cardiotoxicity of amrubicin was far less than that of doxorubicin in a rabbit chronic experimental model (Invest. New Drug; 15, 219–225 (1997)).
Although anthracycline anti-cancer agents have similar structures, diseases which are susceptible to treatment, modes of the action and the like have been known to vary as described below.
Daunorubicin and idarubicin are efficacious against leukemia, however, they are not efficacious against solid cancer. Doxorubicin, epirubicin, pirarubicin and aclarubicin have efficacies toward solid cancer (Nihon Iyakuhinshuu 23th. Ed., 2000, Yakugyou Jiho Co., Ltd.). Daunorubicin and doxorubicin inhibit DNA synthesis and RNA synthesis to the same extent, however, aclarubicin and marceromycin inhibit RNA synthesis to a greater extent than DNA synthesis, with mechanisms to exert anti-canser effects being entirely different each other (JJSHP 27, 1087–1110 (1991)). Although an inhibitory action for cell proliferation of daunorubicin and doxorubicin is attenuated upon reduction of the ketone at 13-position, idarubicin and its reduced form exhibit the action to a similar extent (Cancer Chemother. Pharmacol. 30, 51–57 (1992)). To the contrary, in regard to amrubicin, its reduced form exhibits the action which is stronger than amrubicin (Jpn. J. Cancer Res. 89, 1067–1073 (1998)). Tumor selectivity cannot be achieved by intravenous injection of doxorubicin, however, it was found that intravenous injection of amrubicin can result in the achievement of tumor selectivity in experiments on mouse (Jpn. J. Cancer Res. 89, 1061–1066 (1998)). An intercalation activity of doxorubicin is about ten times stronger than those of amrubicin and amrubicinol (Jpn. J. Cancer Res. 89, 1229–1238 (1998)). Although doxorubicin and daunorubicin largely distribute in cell nuclei, amrubicin and idarubicin largely distribute in cytoplasms (Ann. Haematol. 69, S13–S17 (1994); Jpn. J. Cancer Res. 89, 1229–1238 (1998); and Urol. Res. 25, 125–130 (1997)). Amrubicin and amrubicinol sufficiently stabilize a cleavable complex via topoisomerase II at a concentration which leads to 50% inhibition of cell proliferation, however, doxorubicin does not stabilize the cleavable complex at a concentration which leads to 50% inhibition of cell proliferation (Jpn. J. Cancer Res. 89, 1229–1238 (1998)).
Members in the anthracycline compounds thus vary in terms of their modes of action, and the indication therefor also vary. Among them, doxorubicin, and amrubicin and amrubicinol are extremely closely related in respect of chemical structures, however, the mechanisms of anti-cancer action are widely different.
Recently, an anti-cancer action by combined use of doxorubicin that is an anthracycline compound with Herceptin™ was reported, finding that the combination of doxorubicin with Herceptin™ showed additive effects in an in vitro experiment (M. Pegram et al., Oncogene, 18, 2241–2251 (1999)). However, when doxorubicin and Herceptin™ were used in combination, it was also reported that cardiotoxicity is developed at a high frequency in clinical use (a home page of Genentech, Ltd. on internet). Therefore, such a combination therapy was not always recognized as being effective. Herceptin™ is one of the antibodies directed against a human epidermal cell growth factor receptor 2 protein (hereinafter, referred to as HER2), which has been used as a remedy for breast cancer.